Respiratory syncytial virus (RSV) is the leading cause of acute upper and lower respiratory tract infections (LRTI) in adults, young children and infants. Although at risk populations include the hospitalised, elderly and high-risk adults, RSV is primarily considered to be a paediatric disease due to the prevalence and severity of unfavourable outcomes in infants. Acute LRTI are a leading cause of global childhood mortality and morbidity. Serological evidence indicates that in the western world approximately 95% of all children have been infected with RSV by the age of two and 100% of children have been exposed by the time they reach adulthood.
RSV is a seasonal infectious disease that generally runs from November to March/April in the Northern Hemisphere. In more tropical climates, the annual epidemics are more variable, often coinciding with the wet season. In most cases the RSV infections will only cause minor upper respiratory illness with symptoms resembling that of the common cold. However, severe infection with the virus may result in bronchiolitis or pneumonia which may result in hospitalization or death. Further, since the immune response to RSV infection is not protective, RSV infections reoccur throughout adulthood. Annual re-infection rates in adults of 3-6% have been observed.
RSV is the predominant cause of acute LRTI in infants. Symptoms of RSV infection include bronchiolitis, cough, wheezing, rales (crackling in the lungs), low grade fever (38.3° C.), decreased oral intake and in more advanced cases of infection cyanosis can occur with up to 20% of patients developing an elevated temperature. In a given year, it is estimated that in the United States alone, 4-5 million children under the age of 4 years will develop an acute RSV infection and more than 125,000 infants are hospitalized with an RSV related illness. Between 25-40% of infants with RSV infections will show signs of pneumonia and bronchiolitis. The risk and severity of RSV infections is increased in infants with, for example, chronic co-existing medical conditions such as chronic lung disease, congenital heart disease, those who have been born prematurely and those with immunodeficiency.
In adults and older children, RSV infection has been associated with upper respiratory infection, tracheobronchitis, and otitis media. However, RSV in the institutionalized elderly can be more serious and is characterized by severe pneumonia and mortality rates of up to 20 and 78%, respectively. Adults with a previous history of heart conditions, such as congestive heart failure, or lung conditions, such as chronic obstructive pulmonary disease (COPD), pneumonia and asthma are at a high risk for RSV infection as are immunocompromised adults, for example those receiving haematopoietic stem cell or lung transplants and leukemia patients.
RSV infections place a significant burden on the healthcare system. This is particularly so in the case of infants such as, for example, immunodeficient infants which on average spend twice as long in hospital as other patients with an RSV infection (7-8 days compared to 3-4 days). Hospitalisation of infants with acute RSV-related bronchiolitis or RSV-related pneumonia involves supportive care management with oxygen therapy, fluids to prevent dehydration, nasal suctioning and respiratory support. There is also an economic impact associated with parents taking time away from work to care for their child.
RSV is a member of the order Mononegavirales, which consists of the non-segmented negative strand RNA viruses in the Families Paramyxoviridae, Rhabdoviridae and Filoviridae. RSV of humans (often also termed RSV or HRSV) is a member of the Pneumovirus genus of the sub-family Pneumovirinae within the Family Paramyxoviridae. Based on genetic and antigenic variations in the structural proteins, RSV is classified into two subgroups, A and B (Mufson, M. et al., J. Gen. Virol. 66:2111-2124). Other members of the Pneumovirus genus include viruses such as bovine RSV (BRSV), ovine RSV (ORSV) and pneumonia virus of mice (PVM) amongst others.
In addition to the genome features described above, family characteristics include a lipid envelope containing one or more glycoprotein species considered to be associated with attachment and entry of the host cell. Entry is considered to require a process by which the viral envelope fuses with the membrane of the host cell. Fusion of infected cells with, for example, their neighbours, can also result in the formation of fused multinucleate cells known as syncytia in some cases. The fusion process is believed to be glycoprotein mediated and is a feature shared with diverse enveloped viruses in other taxonomic groups. In the case of the Paramyxoviridae viruses of all genera characteristically express a fusion glycoprotein (F) which mediates membrane fusion.
The only small molecule drug currently approved for the treatment of severe RSV is the antiviral medication, Virazole® (ribavirin solution for inhalation). This agent has a broad spectrum antiviral with virustatic effects, and acts by inhibiting RSV replication. Unfortunately, due to its toxicity, administration of the agent is confined to a hospital setting. Its administration is further complicated by the need to follow a strict procedural process when administering the agent in order to minimise the likelihood of certain adverse affects. The agent has a number of adverse effects including sudden deterioration of respiratory function (bronchiospasm). Virazole is rarely prescribed due to its cost and potential toxicity. The efficacy of Virazole has remained controversial.
In the absence of an effective RSV antiviral therapy a number of preventative strategies have been investigated. There are no vaccines licensed for RSV but some success has been achieved in the area of prevention for infants at high risk of serious lower respiratory tract disease caused by RSV, as well as a reduction of LRTIs. One immunoglobulin-based therapy approved to protect high-risk infants from serious LRTIs is RSV-IGIV (RSV-immunoglobulin intravenous, also known as RespiGam™). RespiGam was licensed by the Food and Drug Administration in January 1996 for prevention of severe RSV lower respiratory tract disease in infants and children younger than 24 months with chronic lung disease (CLD) or a history of preterm birth (≦35 weeks' gestation). Synagis® (palivizumab) is another immunoglobulin-based therapy, more specifically, a monoclonal antibody which is indicated for the preventing RSV-related serious lower tract disease in high risk paediatric patients. In June 1998, the Food and Drug Administration approved Synagis for administration as a monthly intramuscular injection commencing before the onset of the RSV season and continuing for a total of five doses. However difficulties with administration and its high cost is prohibitive to widespread use. Further, the American Association of Paediatricians (AAP) recently updated its recommendations for use of Synagis the effect of which further restricts the use to infants at the highest risk of hospitalisation during times according to likely RSV circulation. Approximately 70% of the infant population hospitalised with severe RSV disease are term infants, which in the absence of approval to treat, are not candidates for receiving Synagis.
Accordingly, there remains an ongoing need for new compounds that are useful in the treatment of RSV infections.
WO2008/037011 describes compounds that are useful in the treatment of RSV infections. The compounds of the present invention fall within the generic scope of WO2008/037011, but are not specifically disclosed therein. The inventors of the present invention have discovered a novel class of compounds which possess properties considered to be desirable in a drug-like compound suitable for the treatment of RSV infections in humans. Desirable properties include potency against RSV; enhanced aqueous solubility; good stability in media such as aqueous solutions, blood and plasma; low or intermediate binding to human plasma proteins and low inhibition of the hERG ion channel (e.g. hERG IC50>500 times higher than RSV EC50).